Two preparations of HA have recently been approved for use in the United States as treatment for joint pain in humans with osteoarthritis (OA) of the knee. However, in a recent study using the canine anterior cruciate ligament (ACL) transection model of OA, we found that prophylactic treatment with intra- articular HA injections of an HA preparation led to a striking reduction in the proteoglycan (PG) concentration in articular cartilage in early stages of the disease. Because the PG concentration of cartilage is inversely related to the hydraulic permeability of the tissue and directly related to stiffness of the tissue on compression, the low PG concentration of cartilage from the HA-injected joints suggested that the cartilage was mechanically compromised, and, therefore highly susceptible to further damage. It is essential to know if the observed PG depletion results in rapid OA progression. We propose to explore this possibility and determine if the HA effect is related to the timing of treatment relative to disease onset, i.e., if the loss of PG occurs only with prophylactic treatment, or is a consequence also of therapeutic administration of HA after pathologic changes of OA have developed. We will test the hypothesis that HA injection produces "analgesic arthropathy" in the injected knees; i.e., that HA treatment relieves pain in the unstable knee, permitting the dog to load the limb more aggressively, thereby accelerating cartilage destruction. We will use force plate analysis to determine whether intra-articular HA injection affects the use of the OA knee in dogs subjected to ACL transection. The goal is to determine whether PG depletion in the cartilage is correlated with loading changes following injection of HA. The alternative hypothesis to be tested is that loss of PG results from effects of exogenous HA on the availability of factors in synovial fluid which affect chondrocyte and synoviocyte metabolism. We propose to examine whether HA infection affects the activities of IL-1beta, IL-6, and TGF-beta in OA synovial fluid. In addition to these specific factors, we will determine the effect of the total mixture of factors present in synovial fluids from saline- or HA-injected knees on normal chrondrocyte PG turnover.